title: PET imaging of high-affinity α4β2 nicotinic acetylcholine receptors in humans with 18F-AZAN, a radioligand with optimal brain kinetics.
abstract: We evaluated (-)-2-(6-[(18)F]fluoro-2,3'-bipyridin-5'-yl)-7-methyl-7-aza-bicyclo[2.2.1]heptane ((18)F-AZAN), a novel radiotracer that binds to α4β2 nicotinic acetylcholine receptors (α4β2-nAChRs) and shows high specific binding and rapid and reversible kinetics in the baboon and human brain.
  
  
  METHODS
  We tested safety tolerability and test-retest reliability (n = 5) and proposed initial quantification of (18)F-AZAN receptors in 3 healthy human subjects who had nicotine exposure and 9 who did not. We also present a receptor blocking study in a nicotine subject dosed with the α4β2-nAChR-selective partial agonist varenicline.
  
  
  RESULTS
  Radiation dosimetry PET/CT experiments indicated that most human organs received doses between 0.008 and 0.015 mSv/MBq, with an effective dose of approximately 0.014 mSv/MBq. The tracer rapidly entered the brain, and the peak was reached before 20 min, even for thalamus. Ninety-minute scans were sufficient for (18)F-AZAN to obtain the ratio at equilibrium of specifically bound radioligand to nondisplaceable radioligand in tissue (BPND) using plasma reference graphical analysis, which showed excellent reproducibility of BPND (test-retest variability < 10%) in the nAChR-rich brain regions. Regional plasma reference graphical analysis BP(ND) values exceeded 2 in the midbrain tegmental nuclei, lateral geniculate body, and thalamus for nonsmokers (n = 9) but were less than 1 in the nAChR-poor brain regions. There was a dramatic reduction of (18)F-AZAN brain uptake in smokers and varenicline-treated subjects.
  
  
  CONCLUSIONS
  (18)F-AZAN is a highly specific, safe, and effective PET radioligand for human subjects that requires only 90 min of PET scanning to estimate high-affinity α4β2-nAChR in the living human brain.
authors.affiliation: Department of Radiology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. dfwong@jhmi.edu
authors.forename: Dean F
authors.initials: DF
authors.lastname: Wong
authors.forename: Hiroto
authors.initials: H
authors.lastname: Kuwabara
authors.forename: Jongho
authors.initials: J
authors.lastname: Kim
authors.forename: James R
authors.initials: JR
authors.lastname: Brasic
authors.forename: Wichana
authors.initials: W
authors.lastname: Chamroonrat
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Gao
authors.forename: Heather
authors.initials: H
authors.lastname: Valentine
authors.forename: William
authors.initials: W
authors.lastname: Willis
authors.forename: Anil
authors.initials: A
authors.lastname: Mathur
authors.forename: Mary E
authors.initials: ME
authors.lastname: McCaul
authors.forename: Gary
authors.initials: G
authors.lastname: Wand
authors.forename: Emily G
authors.initials: EG
authors.lastname: Gean
authors.forename: Robert F
authors.initials: RF
authors.lastname: Dannals
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Horti
mesh_terms: D015082:2,2'-Dipyridyl / Q000031:analogs & derivatives* / Q000378:metabolism; D000328:Adult; D000818:Animals; D053961:Azabicyclo Compounds / Q000378:metabolism; D001552:Benzazepines / Q000378:metabolism; D001667:Binding, Competitive; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D005260:Female; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008297:Male; D008875:Middle Aged; D009538:Nicotine / Q000378:metabolism; D018722:Nicotinic Agonists / Q000378:metabolism; D010215:Papio; D049268:Positron-Emission Tomography / Q000379:methods*; D011810:Quinoxalines / Q000378:metabolism; D011874:Radiometry; D011978:Receptors, Nicotinic / Q000378:metabolism*; D015203:Reproducibility of Results; D000068580:Varenicline
chemical_list: C570237:2-(6-fluoro-2,3'-bipyridin-5'-yl)-7-methyl-7-azabicyclo(2.2.1)heptane; D053961:Azabicyclo Compounds; D001552:Benzazepines; D008024:Ligands; D018722:Nicotinic Agonists; D011810:Quinoxalines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D015082:2,2'-Dipyridyl; D009538:Nicotine; D000068580:Varenicline
keywords: PET; human neuroimaging; nicotinic receptors